The effects of tiropramide hydrochloride on Ca(2+)-induced contraction, cytoplasmic free Ca2+ levels and tissue cyclic AMP concentrations were investigated to elucidate the mechanisms of its antispasmodic action in the isolated detrusor from rats. Tiropramide inhibited the Ca2+ (3 mM)-induced contractions of the isolated urinary bladder depolarized in a Ca(2+)-free medium, and the IC50 value was 3.3 x 10(-6) M. When tiropramide was added during the sustained phase of the K+ (60 mM)-contracture, IC50 values of tiropramide for the contraction and the increased fluorescence were 1.9 x 10(-5) M and 16.4 x 10(-5) M, respectively. On the other hand, the IC50 values for the K(+)-induced contraction and fluorescence after pretreatment of the isolated urinary bladder with tiropramide were 2.1 x 10(-5) M and 2.6 x 10(-5) M, respectively. Tissue cyclic AMP levels at 1 min after addition of 10(-5) M tiropramide were significantly increased. Papaverine, IBMX or forskolin potentiated the inhibitory effect of tiropramide on carbachol-induced contraction and its cyclic AMP-elevating effect. However, a good correlation between the degrees of potentiation of the inhibitory effect and the increase in cyclic AMP levels was not observed. The present results suggest that the smooth muscle relaxant activity of tiropramide in the isolated detrusor from rats may be intimately associated with predominant inhibition of Ca2+ influx and, to a lesser extent, an increase in intracellular cyclic AMP levels.
Pharmacokinetics: Bioavailability: Tiropramide in human plasma was determined by a gas chromatography/nitrogen phosphorus detector. The detection limit of tiropramide was 5 ng/mL. Cmax values of test and reference formulations were 93.9 ± 54.3 and 96.4 ± 51.6 ng/mL, respectively. AUC0→last and AUC0→inf were 330.7 ± 193.9 and 349.5 ± 205.3 ng·h/mL, respectively, for the test formulation, 348.9 ± 207.7 and 380.8 ± 239.0 ng·h/mL, respectively, for the reference formulation. The terminal half-life was 2.34-2.61 h. Bioavailability differences for Cmax and AUC0→last were -2.48% and -5.22%, respectively. Minimum detection differences were less than 20% for both Cmax and AUC0→last. The 90% confidence limits of geometric mean values for logarithmically transformed Cmax and AUCs were within 0.8-1.25. Based on these results, the two formulations of tiropramide are considered to be bioequivalent.